In the production of homogeneous preparations, in particular of biologically active substances, the solubilization of hydrophobic, i.e. slightly water-soluble, substances has become very important in practice.
Solubilization is to be understood as meaning the imparting of solubility to substances which are slightly soluble or insoluble in a certain solvent, in particular water, by surface-active compounds, the solubilizers. Such solubilizers are capable of converting poorly water-soluble or water-insoluble substances into transparent, at most opalescent aqueous solutions without the chemical structure of these substances undergoing a change thereby (cf. Rompp Chemie Lexikon, 9th edition, vol. 5. page 4203, Thieme Verlag, Stuttgart, 1992).
In the solubilizates prepared, the poorly water-soluble or water-insoluble substance is present as a colloidal solution in the molecular associates of the surface-active compounds which form in aqueous solution, such as, for example, hydrophobic domains or micelles. The resulting solutions are stable or metastable single-phase systems which appear optically transparent to opalescent.
In the case of pharmaceutical preparations, the bioavailability and hence the action of drugs can be increased by the use of solubilizers.
A further desirable requirement regarding solubilizers is the ability to form so-called “solid solutions” with slightly soluble substances. The term “solid solution” designates a state in which a substance is dispersed in colloidal form or ideally dispersed in molecular form in a solid matrix, for example a polymer matrix. Such solid solutions, for example when used in solid pharmaceutical administration forms of a slightly soluble active substance, lead to improved release of the active substance. An important requirement regarding said solid solutions is that they are stable even on storage over a relatively long time, i.e. that the active substance does not crystallize. Furthermore, the capacity of the solid solution, in other words the ability to form stable solid solutions having active substance contents which are as high as possible, is also important.
In the formation of solid solutions, the hygroscopicity of the solubilizers also plays an important role in addition to the basic ability of the solubilizers to form solid solutions. Solubilizers which take up too much water from the surrounding air lead to deliquescence of the solid solution and the undesired crystallization of the active substances. Excessively high hygroscopicity can also lead to problems during the processing to give administration forms.
Many known polymeric solubilizers have the disadvantages that they do not form stable solid solutions, in particular when the active substance is present above the saturated concentration in the polymer. As a result, the system is kinetically controlled and the active substance is crystallized in the course of storage. This presents a major problem.
In addition, the known solubilizers and formulations still leave room for improvements, which relates to the solubilization in aqueous systems, in particular biological systems. The oral bioavailability is frequently not increased to the extent which would be desirable in order to achieve a uniform, reproducible action without side effects. Regarding the processability, too, some of the known solubilizers have disadvantages owing to their tendency to become tacky, since they are not sufficiently flowable powders.
A further problem in the case of pharmaceutical preparations of slightly water-soluble active substances is the control of the release. Frequently, it is not the excipient that controls the release in the case of such forms but the crystal properties of the active substance. This means that variations in the particle size of the active substance, differences in the crystal modification and differences in the particle shape have a considerable influence on the dissolution. Since these parameters are difficult to establish exactly, different release rates result. In the case of water-soluble active substances, this problem is not present since the dissolution process of the active substance is considerably faster than the diffusion process which is controlled by a retardant polymer.
With regard to the release, a distinction should be made between instant release (fast-releasing) forms, enteric release (gastric resistant) forms and sustained release (delayed, slowly releasing) forms. Forms which release at least 75% after 1 h are designated as instant release forms. In the case of enteric release forms, slight release takes place in gastric juice (<10% as a rule) but fast release in intestinal fluid. Sustained release forms have a slow release both in gastric juice and in intestinal fluid. The term sustained release form is used when the release is slower than 75% after 3 h.
The slightly water-soluble polymers are to be understood as meaning polymers which are slightly soluble over the entire pH range or at least in a certain pH range. These include so-called sustained release polymers (insoluble as a rule from pH 1 to 14), acidic, gastric resistant polymers (slightly soluble in the acidic pH range), and basic, reverse enteric polymers (slightly soluble in the neutral to basic pH range). See further below for a definition of solubility.
EP-A 876 819 describes the use of copolymers of at least 60% by weight of N-vinylpyrrolidone and amides or esters having long-chain alkyl groups.
EP-A 948 957 describes the use of copolymers of monoethylenically unsaturated carboxylic acids, such as, for example, acrylic acid, and hydrophobically modified comonomers, such as, for example, N-alkyl- or N,N-dialkylamides of unsaturated carboxylic acids having C8-C30-alkyl radicals.
DE-A 199 350 63 discloses polyalkylene oxide-containing graft polymers based on vinyllactams and vinyl acetate and the use thereof as gas hydrate inhibitors.
EP-A 953 347 discloses the use of polyalkylene oxide-containing graft polymers as solubilizers. The graft polymers which are described there and comprise vinyl acetate and polyalkylene oxides are frequently not powders but viscous tacky liquids, which is a disadvantage in use.
WO 2007/051743 discloses the use of water-soluble or water-dispersible copolymers of N-vinyllactam, vinyl acetate and polyethers as solubilizers for pharmaceutical, cosmetic, food, agrotechnical and other technical applications. It is stated therein very generally that the corresponding graft polymers can also be processed in the melt with the active substances.
WO 2009/013202 discloses that such graft polymers of N-vinyllactam, vinyl acetate and polyethers can be melted in an extruder and mixed with pulverulent or liquid active substances, the extrusion at temperatures substantially below the melting point of the active substance being described.
However, a satisfactorily high and simultaneously stable active substance loading cannot be achieved by mixing the molten graft polymers with pulverulent or liquid active substances. In particular, the achievement of a stable X-ray amorphous state of the active substance is not always possible to satisfactory degrees.